the 4th International Satellite Meeting on Carbonic Anhydrase, Parma, Italy, 14 - 17 November 2019
The application of molecular modelling studies to understand the
selectivity and potency of several novel carbonic anhydrase inhibitors
Atilla Akdemir
CAs are metalloenzymes that catalyse the reversible
hydration of carbon dioxide to bicarbonate. Eventhough this is a simple
reaction, it influences physiological pH values and provides bicarbonate for
bioreactions or maintaining the ion balance.[1,2] Many isoforms exist with different tissue
distribution and reaction kinetics and thus CA isoforms are involved in
different physiological processes. For example, hCA IX and XII are
overexpressed in hypoxic tumour cells and are involved in the survival of those
cells. CAs from pathogenic microorganisms are involved in virulence. As such,
selective inhibitors of specific target CAs may be drug candidates for
antimicrobial or anticancer chemotherapy agents.
In both previous and ongoing studies, we synthesized
structurally novel sulfonamides and tested them against carbonic anhydrase (CA)
isozymes that are considered drug targets for anticancer chemotherapeutics or
antimicrobial agents.[3]
Several inhibitors have been obtained that selectively and potently inhibit
tumour-associated hCA IX/XII or pathenic
CAs, while they only show poor inhibition of the widespread off-targets hCA
I/II. Molecular modelling studies have
been performed to understand the reasons behind the selectivity and potency of
these compounds. These results will direct our synthesis efforts in obtaining
inhibitors with higher selectivity and potency.
References
[1] Supuran, C.T.; Scozzafava, A. Carbonic anhydrases as targets for
medicinal chemistry. Bioorganic and
Medicinal Chemistry 2007,
13, 4336-4350
[2] Supuran, C.T. Carbonic anhydrases: novel therapeutic applications for
inhibitors and activators. Nature Reviews
Drug Discovery 2008, 2, 168-181
[3] Demir-Yazıcı, K.; Bua, S.; Akgüneş, N.M.; Akdemir, A.; Supuran, C.T. and
Güzel-Akdemir, Ö. Indole-based hydrazones containing a sulfonamide moiety as
selective inhibitors of tumor-associated human carbonic anhydrase isoforms IX
and XII. Internationl Journal of
Molecular Science 2019, 20(9), 2354